EP2074132B1 - Replacements glycomimétiques pour des hexoses et des n-acétylhexosamines - Google Patents

Replacements glycomimétiques pour des hexoses et des n-acétylhexosamines Download PDF

Info

Publication number
EP2074132B1
EP2074132B1 EP07867214.4A EP07867214A EP2074132B1 EP 2074132 B1 EP2074132 B1 EP 2074132B1 EP 07867214 A EP07867214 A EP 07867214A EP 2074132 B1 EP2074132 B1 EP 2074132B1
Authority
EP
European Patent Office
Prior art keywords
fuc
mmol
gal
solution
added
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
EP07867214.4A
Other languages
German (de)
English (en)
Other versions
EP2074132A2 (fr
Inventor
Beat Ernst
Daniel Schwizer
Arun K. Sarkar
John L. Magnani
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glycomimetics Inc
Original Assignee
Glycomimetics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glycomimetics Inc filed Critical Glycomimetics Inc
Publication of EP2074132A2 publication Critical patent/EP2074132A2/fr
Application granted granted Critical
Publication of EP2074132B1 publication Critical patent/EP2074132B1/fr
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/207—Cyclohexane rings not substituted by nitrogen atoms, e.g. kasugamycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates generally to compounds and discloses methods for obtaining oligosaccharide mimics, and more particularly for obtaining oligosaccharide mimics by incorporating or substituting in a cyclohexane derivative.
  • Naturally occurring monosaccharides and oligosaccharides play a role, or are capable of playing a role, in a variety of biological processes.
  • non-naturally occurring monosaccharides and oligosaccharides may serve to replace or even improve upon their naturally occurring counterparts.
  • Monosaccharides and particularly oligosaccharides may be difficult, and thus costly, to produce. Even where the degree of difficulty to produce is not particularly elevated, the production of monosaccharides and oligosaccharides may still nevertheless be costly. This problem is multiplied where a costly monosaccharide or oligosaccharide needs to be mass produced. While mimics of monosaccharides and oligosaccharides (“glycomimetics”) may improve upon their biological properties, the cost of producing the mimics may not be significantly reduced relative to that which they mimic.
  • the present invention provides a compound having the formula: where Q is H or a physiologically acceptable salt, Me is methyl and Bz is benzoyl.
  • the present invention provides a compound having the formula: where Q is H or a physiologically acceptable salt, Me is methyl and Bz is benzoyl.
  • the present invention provides a compound having the formula: where Q is H or a physiologically acceptable salt, Me is methyl and Bz is benzoyl.
  • the present invention provides a compound having the formula: where Q is H or a physiologically acceptable salt, Me is methyl and Bz is benzoyl.
  • the present invention provides a compound having the formula: where Me is methyl, Et is ethyl and Bz is benzoyl.
  • the present invention provides a compound having the formula: where Me is methyl and Bz is benzoyl.
  • the present invention provides a compound having the formula: where Me is methyl, Et is ethyl and Bz is benzoyl.
  • the present invention provides a compound having the formula: where Me is methyl and Bz is benzoyl.
  • the present invention provides a compound having the formula where Et is ethyl and Bz is benzoyl.
  • the present invention provides a compound having the formula where Bz is benzoyl.
  • the present invention provides a compound as defined in any of claims 1 to 10 for use as an antagonist of E-selectin.
  • the present invention provides the use of a compound as defined in any of claims 1 to 10 for the preparation of a medicament for treating diseases as antagonist of E-selectin.
  • the present invention provides compounds which are useful as antagonists of E-selectin.
  • Acid IV (8.30 g, 65.7 mmol) was placed in a flask purged with argon and suspended in water (180 ml). The reaction mixture was cooled down to 0°C and NaHCO 3 (16.6 g, 197 mmol) was added, followed by a solution of KI (65.4 g, 394 mmol) and iodine (17.5 g, 68.9 mmol) in water (150 ml). The reaction was stirred at r.t. for 24 h and then extracted three times with CH 2 Cl 2 (3x 60 ml). The combined organic layers were washed with a solution of Na 2 S 2 O 3 (50 g) in water (250 ml).
  • Iodolactone V (15.73 g, 62.2 mmol) was dissolved in dry THF (340 ml). Then DBU (14 ml, 93.3 mmol) was added and the mixture was refluxed for 20 h (TLC-control: petroleum ether/Et 2 O, 1:1). The reaction mixture was cooled down to r.t., transferred with Et 2 O (200 ml) into a separation funnel and extracted with aqueous HCl (400 ml, 0.5 M) and brine (400 ml). The aqueous layers were extracted three times with Et 2 O (3x 200 ml). The combined organic layers were dried over Na 2 SO 4 , filtered and concentrated in vacuo (350 mbar).
  • the reaction mixture was diluted with CH 2 Cl 2 (50 ml) and washed twice with HCl 3% (2 x 50 ml).
  • the aqueous layers were extracted with CH 2 Cl 2 (2 x 25 ml) and the combined organic layers were washed with a mixture of brine (80 ml) and water (100 ml).
  • the layers were separated and the aqueous layer was extracted with CH 2 Cl 2 (2 x 50 ml).
  • the combined organic layers were concentrated in vacuo to afford a brown residue still dissolved in a few ml of CH 2 Cl 2 , and was then treated with activated charcoal and filtered through celite. The clear green mixture was concentrated to dryness.
  • XV (7.33 g, 41.4 mmol) was dissolved in Et 2 O (43 ml) in a flame dried flask equipped with a dropping funnel: tert -BuLi (1.7 M in pentane, 133 mmol) was dropwise added at -78 °C over 1 h and 15 min. After complete addition, the clear yellowish mixture was stirred for further 1 h and 30 min at - 78 °C and was then warmed up to -20 °C over 3 hrs and 15 min. The reaction was quenched by addition of satd. solution of NaHCO 3 (50 ml) and stirred for a further hour at room temperature.
  • Tritylether XVII (948 mg, 2.79 mmol) was dissolved under argon atmosphere in CH 2 Cl 2 (30 ml) and NaHCO 3 (281 mg, 3.34 mmol) was added. The mixture was cooled to 0 °C and under stirring m-chloroperbenzoic acid (70 %, 960 mg, 5.56 mmol) was added. After stirring for 1.5 h the reaction temperature was gradually raised to room temperature and the mixture was stirred for another 3.5 h. The reaction was diluted with CH 2 Cl 2 (50 ml) and transferred to a separation funnel. The excess of m-chloroperbenzoic acid was destroyed by washing with satd. solution of Na 2 S 2 O 3 (2 x 150 ml).
  • Copper(I) iodide (99 mg, 2.62 mmol) was dried at high vacuo at 200 °C for 30 minutes, then flushed with argon and suspended in dry diethylether (10 ml). After cooling to - 20 °C MeLi (1.6 M in ether, 3.26 ml, 5.22 mmol) was slowly added and the solution was stirred for 15 minutes. A solution of epoxide anti -XVIII (310 mg, 0.870 mmol) in diethylether (7 ml) was added to the cuprate. After stirring for 30 minutes at -20 °C the reaction mixture was slowly brought to room temperature and stirred for one week.
  • the reaction was diluted with tert -butyl methyl ether (10 ml) and quenched at 0 °C with satd. solution of NaHCO 3 (10 ml).
  • the reaction mixture was further diluted and extracted with tert -butyl methyl ether and satd. solution of NaHCO 3 (each 20 ml).
  • the aqueous layer was extracted twice with tert -butyl methyl ether (2 x 50 ml).
  • the combined organic layers were dried with Na 2 SO 4 and concentrated.
  • the residue was purified by flash chromatography (petroleum ether/EtOAc/Et 3 N, 13:1:0.07) to yield XIX (206 mg, 64 %) as yellowish resin.
  • Pd/C 50 mg, 10 % Pd
  • ethanol 3 ml
  • Compound XXII 101 mg, 79.8 ⁇ mol
  • the reaction was quenched with CH 2 Cl 2 and filtered on celite, washing with methanol.
  • the filtrate was concentrated under vacuum, redissolved in methanol/water (3:1, 4 ml) and lithium hydroxide (100 mg, 4.18 mmol) was added.
  • the reaction was slowly warmed to -50°C over 5 h and then stirred at this temperature for 24 h. After slowly warming the reaction to -30°C over another 21 h the reaction was quenched with a 25% aq. NH 3 /satd. NH 4 Cl (1:9, 20 mL) solution. The mixture was transferred with Et 2 O (30 mL) into a separation funnel and extracted with additional 25% aq. NH 3 /satd. NH 4 Cl (1:9, 30 mL) solution. The layers were separated and the organic layer was washed with brine (50 mL). The aqueous layers were extracted with Et 2 O (2 x 30 mL).
  • a vinyl lithium solution was generated in situ by treating a solution of tetravinyl tin (409 ⁇ L, 2.25 mmol) in THF (3 mL) with n BuLi (2.5 M in hexane, 3.35 mL, 8.38 mmol) during 30 min at 0°C.
  • CuCN (373 mg, 4.16 mmol) in THF (8 mL) was treated with the vinyl lithium solution and BF 3 etherate (209 ⁇ L, 1.66 mmol) in THF (1.5 mL) according to general procedure A.
  • a solution of A-IV (90.0 mg, 0.161 mmol) in THF (4 mL) was added to Pd/C (45.2 mg, 10% Pd) under argon.
  • the mixture was hydrogenated under atmospheric pressure at r.t. After 30 min the reaction was filtered through celite, concentrated under reduced pressure and purified by column chromatography (toluene/petroleum ether/ethyl acetate, 7:7:1 to 5:5:1) to yield A-V (69.8 mg, 77%) as a colorless solid.
  • thioglycoside A-VI (112 mg, 0.144 mmol) and glycosyl acceptor A-V (61.6 mg, 0.110 mmol) in dry CH 2 Cl 2 (4 mL) were added via syringe to activated 3A molecular sieves (1 g).
  • a suspension of DMTST (87.0 mg, 0.337 mmol) and activated 3A molecular sieves (500 mg) in CH 2 Cl 2 (2 mL) was prepared in a second flask. Both suspensions were stirred at r.t. for 4 h, then the DMTST suspension was added via syringe to the other suspension with some additional CH 2 Cl 2 (1 mL). The reaction was stopped after 49.5 h and work-up and purification according to general procedure C afforded A-VII (110 mg, 78%) as a colorless foam.
  • A-VII (38.2 mg, 29.9 ⁇ mol) was hydrogenated with Pd(OH) 2 /C (50 mg, 10% Pd) in dioxane/H 2 O (4:1, 3.75 mL) according to general procedure D. After 24 h the reaction mixture was filtered through celite and evaporated to dryness. The residue was redissolved in methanol (5 mL) and sodium methoxide (74.6 ⁇ mol in 73 ⁇ l MeOH) was added. After stirring at r.t. for 16 h the reaction was quenched by addition of acetic acid (8.5 ⁇ L). The mixture was concentrated in vacuo and purified by preparative, reversed-phase HPLC to afford A-VIII (16.3 mg, 77%) as a colorless solid.
  • a cPrLi solution was generated in situ by treating a solution of bromocyclopropane (370 ⁇ L, 4.63 mmol) in THF (4 mL) with t BuLi (1.7 M in pentane, 5.45 mL, 9.27 mmol) during 80 min at -78°C.
  • CuCN 210 mg, 2.34 mmol
  • THF 5 mL
  • BF 3 etherate 115 ⁇ L, 0.914 mmol
  • thioglycoside A-VI (228 mg, 0.292 mmol) and glycosyl acceptor B-II (129 mg, 0.225 mmol) in dry CH2Cl 2 (8 mL) were added via syringe to activated 3A molecular sieves (2 g).
  • a suspension of DMTST (177 mg, 0.685 mmol) and activated 3A molecular sieves (1 g) in CH 2 Cl 2 (4 mL) was prepared in a second flask. Both suspensions were stirred at r.t. for 4 h, then the DMTST suspension was added via syringe to the other suspension with some additional CH 2 Cl 2 (2 mL). The reaction was stopped after 48 h and work-up and purification according to general procedure C afforded B-III (253 mg, 87%) as a colorless foam.
  • B-III (100 mg, 77.7 ⁇ mol) was hydrogenated with Pd(OH) 2 /C (52 mg, 10% Pd) in dioxane/H 2 O (4:1, 3.75 mL) according to general procedure D. After 24 h the mixture was filtered through celite and hydrogenated with fresh Pd(OH) 2 /C (50 mg) for another 48 h. The reaction mixture was filtered through celite and evaporated to dryness. The residue was redissolved in methanol (5 mL) and sodium methoxide (194 ⁇ mol in 190 ⁇ l MeOH) was added. After stirring at r.t. for 16 h the reaction was quenched by addition of acetic acid (22 ⁇ L). The mixture was concentrated in vacuo and purified by preparative, reversed-phase HPLC to afford B-IV (40.5 mg, 72%) as a colorless solid.
  • thioglycoside A-VI (218 mg, 0.279 mmol) and glycosyl acceptor C-II (126 mg, 0.215 mmol) in dry CH 2 Cl 2 (8 mL) were added via syringe to activated 3A molecular sieves (2 g).
  • a suspension of DMTST (166 mg, 0.644 mmol) and activated 3A molecular sieves (1 g) in CH 2 Cl 2 (4 mL) was prepared in a second flask. Both suspensions were stirred at r.t. for 4.5 h, then the DMTST suspension was added via syringe to the other suspension with some additional CH 2 Cl 2 (2 mL). The reaction was stopped after 65.5 h and work-up and purification according to general procedure C afforded C-III (224 mg, 80%) as a colorless foam.
  • A-IV (106 mg, 0.189 mmol) was dissolved in CH 2 Cl 2 (5 mL) and Grubbs cat. 2 nd gen. (16.0 mg 18.8 ⁇ mol) and methyl acrylate (171 ⁇ L, 1.90 mmol) were added. The reaction was heated under reflux for 9 d. After 1 d, 2 d and 7 d additional Grubbs cat. 2 nd gen. (each 16.0 mg, 18.8 ⁇ mol) and methyl acrylate (each 171 ⁇ L, 1.90 mmol) were added.
  • thioglycoside A-VI 47.9 mg, 61.3 ⁇ mol
  • glycosyl acceptor D-I 29.1 mg, 47.0 ⁇ mol
  • a suspension of DMTST 37.6 mg, 146 ⁇ mol
  • activated 3A molecular sieves 250 mg
  • CH 2 Cl 2 2 mL
  • D-III (46.0 mg, 34.4 ⁇ mol) was hydrogenated with Pd(OH) 2 /C (25 mg, 10% Pd) in dioxane/H 2 O (4:1, 3.75 mL) according to general procedure D. After 42 h the mixture was filtered through celite and hydrogenated with fresh Pd(OH) 2 /C (27 mg) for additional 24 h. The reaction mixture was filtered through celite and evaporated to dryness. The residue was redissolved in methanol (3 mL) and sodium methoxide (51.6 ⁇ mol in 55 ⁇ l MeOH) was added. After stirring at r.t. for 16 h the reaction was quenched by addition of acetic acid (6 ⁇ L). The mixture was concentrated in vacuo and purified by preparative, reversed-phase HPLC to afford D-III (19.2 mg, 73%) as a colorless solid.
  • rac - E-VI (135 mg, 0.287 mmol) was suspended in MeOH (5 mL). Et 3 N (1 mL) was added and the reaction stirred for 1 h. The solvents were evaporated in vacuo and the residue was purified by MPLC on silica (toluene/ethyl acetate, 6:0 to 6:1) affording rac - E-VII (63.2 mg, 80%) as a white solid.
  • thioglycoside A-VI 125 mg, 0.161 mmol
  • glycosyl acceptor E-VIII 71.4 mg, 0.121 mmol
  • a suspension of DMTST 120 mg, 0.465 mmol
  • activated 4A molecular sieves 500 mg
  • CH 2 Cl 2 2 mL
  • Both suspensions were stirred at r.t. for 2 h, before adding the DMTST suspension via syringe to the other suspension with some additional CH 2 Cl 2 (1 mL).
  • Second compound (5 mg) was mixed with mPEG-nitrophenylcarbonate (5K) 75 mg , triethylamine 5 ul in DMF (2 mL). The resulting mixture was stirred at rt for 3 h. The solvent was removed at reduced pressure. The residue was purified on C-18 to afford 40 mg product.
  • Second compound (20 mg) from Example 11 was mixed with 200 mg 4-arm PEG glutamidylsuccinate , triethylamine 5 ul and DMF 2 mL. The resulting mixture was stirred at rt for 2 hr. After removing the solvent, the residue was purified on HPLC to afford the product.
  • E-selectin Protocol The inhibition assay to screen glycomimetic antagonists of E-selectin is a competitive binding assay, which allows the determination of IC 50 values. Briefly, E-selectin/Ig chimera is immobilized by incubation at 37°C in 96 well microtiter plates for 2 hours. To reduce nonspecific binding, bovine serum albumin is added to each well and incubated at room temperature for 2 hours. The plate is washed and serial dilutions of the test compounds are added to the wells in the presence of conjugates of biotinylated, sLe a polyacrylamide with streptavidin/horseradishperoxidase and incubated for 2 hours at room temperature.
  • the peroxidase substrate 3,3',5,5' tetramethylbenzidin (TMB) is added. After 3 minutes, the enzyme reaction is stopped by the addition of H 3 PO 4 and the absorbance of light at a wavelength of 450 nm is determined. The concentration of test compound required to inhibit binding by 50% is determined and reported as the IC 50 value for each glycomimetic E-selectin antagonist. In addition to reporting the absolute IC 50 value as measured above, relative IC 50 values are determined by a ratio of the IC 50 measured for the test compound to that of a glycomimetic internal control (reference) for each assay. The results from the testing in this assay of several of the compounds disclosed herein are shown below. Compounds IC 50 ( ⁇ M) rIC 50 #1 15.5 0.076 #2 10.1 0.049 #3 3.75 0.027

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
  • Polysaccharides And Polysaccharide Derivatives (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (12)

  1. Composé ayant la formule :
    Figure imgb0031
     où Q représente H ou un sel physiologiquement acceptable, Me représente un groupe méthyle et Bz représente un groupe benzoyle.
  2. Composé ayant la formule :
    Figure imgb0032
     où Q représente H ou un sel physiologiquement acceptable, Me représente un groupe méthyle et Bz représente un groupe benzoyle.
  3. Composé ayant la formule :
    Figure imgb0033
     où Q représente H ou un sel physiologiquement acceptable, Me représente un groupe méthyle et Bz représente un groupe benzoyle.
  4. Composé ayant la formule :
    Figure imgb0034
     où Q représente H ou un sel physiologiquement acceptable, Me représente un groupe méthyle et Bz représente un groupe benzoyle.
  5. Composé ayant la formule :
    Figure imgb0035
     où Me représente un groupe méthyle, Et représente un groupe éthyle et Bz représente un groupe benzoyle.
  6. Composé ayant la formule :
    Figure imgb0036
     où Me représente un groupe méthyle et Bz représente un groupe benzoyle.
  7. Composé ayant la formule :
    Figure imgb0037
     où Me représente un groupe méthyle, Et représente un groupe éthyle et Bz représente un groupe benzoyle.
  8. Composé ayant la formule :
    Figure imgb0038
     où Me représente un groupe méthyle et Bz représente un groupe benzoyle.
  9. Composé ayant la formule :
    Figure imgb0039
     où Et représente un groupe éthyle et Bz représente un groupe benzoyle.
  10. Composé ayant la formule :
    Figure imgb0040
     où Bz représente un groupe benzoyle.
  11. Composé selon l'une quelconque des revendications 1 à 10, pour une utilisation en tant qu'antagoniste de la sélectine E.
  12. Utilisation d'un composé selon l'une quelconque des revendications 1 à 10, pour la préparation d'un médicament destiné au traitement de maladies en tant qu'antagoniste de la sélectine E.
EP07867214.4A 2006-10-12 2007-10-09 Replacements glycomimétiques pour des hexoses et des n-acétylhexosamines Active EP2074132B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US85146706P 2006-10-12 2006-10-12
PCT/US2007/021541 WO2008060378A2 (fr) 2006-10-12 2007-10-09 Replacements glycomimétiques pour des hexoses et des n-acétylhexosamines

Related Child Applications (1)

Application Number Title Priority Date Filing Date
EP11006039.9 Division-Into 2011-07-22

Publications (2)

Publication Number Publication Date
EP2074132A2 EP2074132A2 (fr) 2009-07-01
EP2074132B1 true EP2074132B1 (fr) 2013-05-15

Family

ID=39402172

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07867214.4A Active EP2074132B1 (fr) 2006-10-12 2007-10-09 Replacements glycomimétiques pour des hexoses et des n-acétylhexosamines

Country Status (5)

Country Link
US (2) US7964569B2 (fr)
EP (1) EP2074132B1 (fr)
JP (2) JP5298020B2 (fr)
CA (1) CA2666103C (fr)
WO (1) WO2008060378A2 (fr)

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2008336249B2 (en) 2007-12-10 2015-01-29 The University Of Queensland Treatment and prophylaxis
CN102421441B (zh) 2009-05-01 2015-04-01 糖模拟物有限公司 E-选择蛋白和cxcr4趋化因子受体的异双功能抑制剂
WO2011040574A1 (fr) * 2009-09-30 2011-04-07 国立大学法人京都大学 Procédé pour produire un dérivé d'azétidinylméthoxypyridine et utilisation du dérivé d'azétidinylméthoxypyridine
WO2012037034A1 (fr) 2010-09-14 2012-03-22 Glycomimetics, Inc. Antagonistes de l'e-sélectine
WO2012061662A1 (fr) 2010-11-03 2012-05-10 Glycomimetics, Inc. Inhibiteurs glycomimétiques-peptidomimétiques de sélectines e et de récepteurs de chimiokine cxcr4
WO2013096926A1 (fr) 2011-12-22 2013-06-27 Glycomimetics, Inc. Composés antagonistes de la sélectine e, compositions et méthodes d'utilisation
EP2928476B1 (fr) 2012-12-07 2018-02-14 GlycoMimetics, Inc. Composés, compositions et procédés utilisant des antagonistes d'e-sélectine pour la mobilisation de cellules hématopoïétiques
WO2014149837A1 (fr) * 2013-03-15 2014-09-25 Glycomimetics, Inc. Composés et procédés pour améliorer la disponibilité orale de glycomimétiques
WO2015109049A1 (fr) * 2014-01-17 2015-07-23 Glycomimetics, Inc. Antagonistes d'e-sélectines modifiés par formation de macrocycles sur le galactose
ES2754549T3 (es) 2014-12-03 2020-04-20 Glycomimetics Inc Inhibidores heterobifuncionales de E-selectinas y receptores de quimioquinas CXCR4
WO2017127422A1 (fr) 2016-01-22 2017-07-27 Glycomimetics, Inc. Inhibiteurs glycomimétiques des lectines pa-il et pa-iil
US11291678B2 (en) 2016-03-02 2022-04-05 Glycomimetics, Inc Methods for the treatment and/or prevention of cardiovascular disease by inhibition of E-selectin
EP3497131B1 (fr) 2016-08-08 2022-03-09 GlycoMimetics, Inc. Combinaison d'inhibiteurs des points de contrôle des lymphocytes t avec des inhibiteurs de e-sélectine ou de cxcr4, ou avec des inhibiteurs hétérobifonctionnels de e-sélectine et de cxcr4
US11072625B2 (en) * 2016-10-07 2021-07-27 Glycomimetics, Inc. Highly potent multimeric e-selectin antagonists
WO2018169853A1 (fr) * 2017-03-15 2018-09-20 Glycomimetics, Inc. Dérivés de galactopyranosyle-cyclohexyle utilisés en tant qu'antagonistes d'e-sélectine
EP3717013A1 (fr) 2017-11-30 2020-10-07 GlycoMimetics, Inc. Méthodes de mobilisation de lymphocytes infiltrant la moelle et leurs utilisations
EP3732186A1 (fr) 2017-12-29 2020-11-04 GlycoMimetics, Inc. Inhibiteurs hétérobifonctionnels de e-sélectine et de galectine -3
CN111867601A (zh) 2018-03-05 2020-10-30 糖模拟物有限公司 用于治疗急性髓系白血病及相关病症的方法
WO2020139962A1 (fr) 2018-12-27 2020-07-02 Glycomimetics, Inc. Inhibiteurs hétérobifonctionnels d'e-sélectine et de galectine-3
CN114340736A (zh) 2019-04-24 2022-04-12 糖模拟物有限公司 E-选择蛋白、半乳凝素-3和/或cxcr4趋化因子受体的半乳糖-连接的多聚体糖模拟物抑制剂

Family Cites Families (113)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4471057A (en) * 1981-06-30 1984-09-11 The Wistar Institute Detection of colorectal carcinoma
DK17885D0 (da) * 1985-01-14 1985-01-14 Karlsson Karl Anders Antiviralt middel
US4876199A (en) * 1985-04-04 1989-10-24 Fred Hutchinson Cancer Research Center Hybridomas producing monoclonal antibodies to mono-, di-, and trifucosylated type 2 chain
US4851511A (en) * 1986-01-30 1989-07-25 Fred Hutchinson Cancer Research Center Monoclonal antibody that specifically binds to disialosyl Lea
US4925796A (en) * 1986-03-07 1990-05-15 Massachusetts Institute Of Technology Method for enhancing glycoprotein stability
DE3787403D1 (de) * 1986-05-09 1993-10-21 Pulverer Gerhard Verwendung von spezifischen Monosacchariden zur Herstellung eines Arzneimittels zur Verhinderung von Metastasen maligner Tumore.
US5538724A (en) 1987-08-11 1996-07-23 The Board Of Trustees For The Leland Stanford Junior Univ. Method of control leukocyte extravasation
US5464778A (en) 1989-03-08 1995-11-07 Board Of Regents Of The University Of Oklahoma Glycoprotein ligand for P-selectin and methods of use thereof
US6033665A (en) 1989-09-27 2000-03-07 Elan Pharmaceuticals, Inc. Compositions and methods for modulating leukocyte adhesion to brain endothelial cells
US6001988A (en) 1990-06-11 1999-12-14 Nexstar Pharmaceuticals, Inc. High affinity nucleic acid ligands to lectins
US6280932B1 (en) 1990-06-11 2001-08-28 Gilead Sciences, Inc. High affinity nucleic acid ligands to lectins
US5576305A (en) 1990-06-15 1996-11-19 Cytel Corporation Intercellular adhesion mediators
US5753631A (en) 1990-06-15 1998-05-19 Cytel Corporation Intercellular adhesion mediators
US6387884B1 (en) 1990-06-18 2002-05-14 Stanford University Leukocyte homing modulation
US6391857B1 (en) 1990-06-18 2002-05-21 Stanford University Methods and compositions for endothelial binding
US5648344A (en) 1990-07-30 1997-07-15 Glycomed Incorporated Methods of treating inflammation using selection binding compounds
US5143712A (en) * 1990-07-30 1992-09-01 Glycomed Incorporated Method of determining a site of inflammation utilizing elam-1 ligands
US5211937A (en) * 1990-07-30 1993-05-18 Glycomed Incorporated Method of determining a site of inflammation utilizing elam-1 ligands
US5789573A (en) 1990-08-14 1998-08-04 Isis Pharmaceuticals, Inc. Antisense inhibition of ICAM-1, E-selectin, and CMV IE1/IE2
CZ96893A3 (en) 1990-11-23 1993-12-15 Gen Hospital Corp Inhibition of adhesive protein cells and their carbohydrates interaction
US5151360A (en) * 1990-12-31 1992-09-29 Biomembrane Institute Effect of n,n,n-trimethylsphingosine on protein kinase-c activity, melanoma cell growth in vitro, metastatic potential in vivo and human platelet aggregation
US6309639B1 (en) 1991-02-05 2001-10-30 The Board Of Regents Of The University Of Oklahoma Method for inhibiting an inflammatory response using antibodies to P-selectin glycoprotein ligand
US6124267A (en) 1991-02-05 2000-09-26 Southpac Trust Internationals, Inc. O-glycan inhibitors of selectin mediated inflammation derived from PSGL-1
US6121233A (en) 1991-04-19 2000-09-19 John L. Magnani Methods for the inhibition of cancer metastasis mediated by endothelial adhesion molecules
EP0584229B1 (fr) 1991-05-06 2003-07-23 Genentech, Inc. Un ligand de selectine
US5318890A (en) 1991-05-06 1994-06-07 The Regents Of The University Of California Assays for inhibitors of leukocyte adhesion
US5646123A (en) 1991-06-10 1997-07-08 Alberta Research Council Time dependent administration of oligosaccharide glycosides related to blood group determinants having a type I or type II core structure in reducing inflammation in a sensitized mammal arising form exposure to an antigen
US5580858A (en) 1991-06-10 1996-12-03 Alberta Research Council Immunosuppressive and tolerogenic modified Lewisx compounds
US5352670A (en) 1991-06-10 1994-10-04 Alberta Research Council Methods for the enzymatic synthesis of alpha-sialylated oligosaccharide glycosides
CA2118695A1 (fr) 1991-09-10 1993-03-18 George A. Heavner Inhibiteurs peptidiques de l'inflammation mediee par les selectines
US5268364A (en) * 1991-12-12 1993-12-07 The Biomembrane Institute Method for inhibiting selectin-dependent adhesion of leukocytes and platelets by O-glycosylation modification
JPH07501828A (ja) 1991-12-18 1995-02-23 セントコー，インコーポレイテッド セレクチン類で仲介される炎症のペプチド阻害剤
US5591835A (en) 1992-06-29 1997-01-07 Glycomed Incorporated Substituted lactose derivatives
CA2100412A1 (fr) 1992-07-15 1994-01-16 Yutaka Yamada Derives de glycolipides
CA2144180A1 (fr) 1992-09-08 1994-03-17 George A. Heavner Inhibiteurs peptidiques de l'adhesion cellulaire
US5519008A (en) 1992-09-10 1996-05-21 Glycomed Incorporated Derivatives of triterpenoid acids as inhibitors of cell-adhesion molecules ELAM-1 (E-selectin) and LECAM-1 (L-selectin)
WO1994006442A1 (fr) 1992-09-11 1994-03-31 The Regents Of The University Of California Ligands sulfates pour les l-selectines et utilisation de chlorates et/ou de sulfatases pour le traitement de l'inflammation
US5695752A (en) 1992-09-11 1997-12-09 The Regents Of The University Of California Treating inflammation via the administration of specific sulfatase enzymes and/or sulfation inhibitor
US5843707A (en) 1992-10-23 1998-12-01 Genetics Institute, Inc. Nucleic acid encoding a novel P-selectin ligand protein
US6277975B1 (en) 1992-10-23 2001-08-21 Genetics Institute, Inc. Fusions of P-selectin ligand protein and polynucleotides encoding same
EP0601417A3 (fr) 1992-12-11 1998-07-01 Hoechst Aktiengesellschaft Physiologiquement compatible et dégradable bloques de récepteur d'hydrate de carbone à base de polymère, procédé de leur préparation et leur utilisation
WO1994014836A1 (fr) 1992-12-18 1994-07-07 Centocor, Inc. Inhibiteurs peptidiques de liaison de selectine
JP3887011B2 (ja) 1992-12-29 2007-02-28 ジェネンテク，インコーポレイテッド ＩＦＮ−γインヒビターによる炎症性腸疾患の処置
US5412123A (en) 1993-02-08 1995-05-02 Glycomed Incorporated Anthraquinone and anthracene derivatives as inhibitors of the cell-adhesion molecules of the immune system
JP2716657B2 (ja) * 1993-02-26 1998-02-18 株式会社ディ・ディ・エス研究所 接着分子ｅｌａｍ‐１に特異的結合能を有する化合物
US5763413A (en) 1993-03-04 1998-06-09 Mect Corporation Lewis-associated compound, process for producing the same, and anti-inflammatory
US5527890A (en) 1993-04-16 1996-06-18 Glycomed Incorporated Derivatives of triterpenoid acids and uses thereof
PL176272B1 (pl) 1993-05-14 1999-05-31 Cytel Corp Analogi sialilowe Le jako inhibitory adhezji komórkowej
US5854218A (en) 1993-05-14 1998-12-29 Cytel Corporation Sialyl Lex analogues as inhibitors of cellular adhesion
US5811404A (en) 1993-05-14 1998-09-22 Cytel Corporation Sialyl Lex analogues as inhibitors of cellular adhesion
US5527785A (en) 1993-05-14 1996-06-18 The Regents Of The University Of California Selectin receptor modulating compositions
JP3662021B2 (ja) 1993-05-17 2005-06-22 アーヴァント イミュノセラピューティクス インコーポレイテッド 補体関連蛋白質および炭水化物よりなる組成物、ならびに該組成物の製法および使用方法
US5976540A (en) 1993-05-17 1999-11-02 T Cell Sciences, Inc. Compositions comprising complement related proteins and carbohydrates, and methods for producing and using said compositions
US5646248A (en) 1993-06-08 1997-07-08 La Jolla Cancer Research Foundation E-selection binding soluble lamp-1 polypeptide
US5837689A (en) 1993-06-16 1998-11-17 Glycomed Incorporated Sialyl lewis-x mimetics containing naphthyl backbones
US5789385A (en) 1993-06-16 1998-08-04 Glycomed Incorporated Sialyl Lewisx mimetics containing phenyl backbones
US5750508A (en) 1993-06-16 1998-05-12 Glycomed Incorporated Sialic acid/fucose based medicaments
US5658880A (en) 1993-06-16 1997-08-19 Glycomed Incorporated Sialic acid/fucose based medicaments
US5679321A (en) 1993-06-17 1997-10-21 Glycomed Incorporated Sialic acid/fucose based medicaments
US5559103A (en) 1993-07-21 1996-09-24 Cytel Corporation Bivalent sialyl X saccharides
US5508387A (en) 1993-08-04 1996-04-16 Glycomed Incorporated Selectin binding glycopeptides
WO1995005830A1 (fr) 1993-08-20 1995-03-02 The Regents Of The University Of California Agents anti-inflammatoires polyanioniques
US5464815A (en) 1993-09-08 1995-11-07 Genentech, Inc. Inhibition of heparin-binding
CA2173990A1 (fr) 1993-10-12 1995-04-20 Narasinga Rao Banque de glyco-peptides permettant d'identifier des inhibiteurs d'adherence intercellulaire
US5783693A (en) 1993-11-19 1998-07-21 The Regents Of The University Of California Methods for synthesizing sulfated disaccharide inhibitors of selectins
WO1995014787A1 (fr) 1993-11-22 1995-06-01 Centocor, Inc. Peptides inhibiteurs de liaison a la selectine
US5663151A (en) 1994-03-04 1997-09-02 Bristol-Myers Squibb Company Sulfated α-glycolipid derivatives as cell adhesion inhibitors
EP0671409A3 (fr) 1994-03-11 1996-06-12 Hoechst Ag Dérivés de l'acide malonique ayant des propriétés anti-adhésives.
DE4408248A1 (de) 1994-03-11 1995-09-14 Hoechst Ag Physiologisch verträgliche und physiologisch abbaubare Kohlenhydrat-Mimetika, ein Verfahren zur Herstellung und ihre Verwendung
US5444050A (en) 1994-04-29 1995-08-22 Texas Biotechnology Corporation Binding of E-selectin or P-selectin to sialyl Lewisx or sialyl-Lewisa
HUT77345A (hu) 1994-04-29 1998-03-30 Texas Biotechnology Corporation E-szelektin, P-szelektin vagy L-szelektin szialil-Lewis x-hez vagy szialil-Lewis a-hoz kapcsolódását gátló mannopiranoziloxi-bifenil származékok és ezeket tartalmazó gyógyszerkészítmények
US5486536A (en) 1994-08-15 1996-01-23 The Regents Of The University Of Michigan Sulfatides as anti-inflammatory compounds
JPH0899989A (ja) 1994-09-30 1996-04-16 Akira Hasegawa 新規糖脂質誘導体およびその製造用中間体
DE4436164A1 (de) 1994-10-10 1996-04-11 Hoechst Ag Neue Kohlenhydratkonjugate als Inhibitoren der Zelladhäsion
US5686426A (en) 1994-11-17 1997-11-11 Bristol-Myers Squibb Company Dicarboxymethylated glycolipid derivatives as cell adhesion inhibitors
US6492332B1 (en) 1995-12-12 2002-12-10 Omeros Corporation Irrigation solution and methods for inhibition of tumor cell adhesion, pain and inflammation
US5639734A (en) 1994-12-20 1997-06-17 Esko; Jeffrey D. Disaccharide inflammation inhibitors and uses thereof
US20020040008A1 (en) 1995-01-24 2002-04-04 Wagner Denisa D. Method for treating and preventing atherosclerosis
US5736533A (en) 1995-06-07 1998-04-07 Neose Technologies, Inc. Bacterial inhibition with an oligosaccharide compound
TR199701728T1 (xx) * 1995-06-29 1998-03-21 Novartis Ag Sialil-Lewis X ve sialil-Lewis A taklitleri olarak digikosilatlanm�� 1,-2-dioller.
US5876715A (en) 1995-08-17 1999-03-02 The Biomembrane Institute Antibodies that bind novel carbohydrate ligands (myelorollins) that cause E-selectin dependent cell rolling, and uses thereof
DE19532902A1 (de) 1995-09-06 1997-03-13 Hoechst Ag Neuartige Glycomimetika als Selektin-Antagonisten und daraus hergestellte entzündungshemmend wirkende Arzneimittel
DE19537334A1 (de) 1995-10-09 1997-04-10 Hoechst Ag Antiadhäsive Piperidin- und Pyrrolidin-Carbonsäuren
EP0859005A1 (fr) 1995-10-26 1998-08-19 Kanebo, Ltd. Derives de la fucose, medicaments dont ils forment le principe actif, et leurs intermediaires de fabrication
US5747463A (en) 1995-11-13 1998-05-05 Bristol-Myers Squibb Company Malonate derivatives of glycolipids as cell adhesion inhibitors
DE19602355A1 (de) 1996-01-24 1997-07-31 Hoechst Ag Mehrfach fucosylierte Dicarbonsäuren mit antiadhäsiven Eigenschaften
DE69738731D1 (de) 1996-01-30 2008-07-10 Glycomimetics Inc SIALYL-LEWISa UND SIALYL-LEWISx EPITOPE ANALOGE
AU1542397A (en) 1996-01-30 1997-08-22 Novartis Ag Sialyl-lewisa and sialyl-lewisx epitope analogues
AU718317B2 (en) 1996-03-01 2000-04-13 Regents Of The University Of California, The Inhibition of selectin binding
US5710023A (en) 1996-03-01 1998-01-20 Genetics Institute, Inc. IL-13 cytokine receptor chain
US5654412A (en) 1996-05-29 1997-08-05 Glycomed Incorporated Processes for the synthesis of sialyl Lewisx compounds
US5994402A (en) 1996-06-05 1999-11-30 Rotstein; Ori D. Anti-inflammatory and anti-pyretic method
US5919768A (en) 1996-06-26 1999-07-06 Texas Biotechnology Corporation Di- and trivalent small molecule selectin inhibitors
US5830871A (en) 1996-10-28 1998-11-03 The Scripps Research Institute Inhibitors of E-, P- and L-selectin binding
GB9618520D0 (en) 1996-09-05 1996-10-16 Chiroscience Ltd Compounds and their therapeutic use
US6110897A (en) 1996-10-10 2000-08-29 Glycorex Ab Antiinflammatory cell adhesion inhibitors
CA2281684C (fr) 1997-02-28 2006-08-29 The Regents Of The University Of California Inhibition de la liaison entre cellules au moyen d'ensembles lipidiques
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
SE9701127D0 (sv) 1997-03-26 1997-03-26 Karolinska Innovations Ab Antigenic fusionprotein carrying GALal, 3GAL epitopes
US5916910A (en) 1997-06-04 1999-06-29 Medinox, Inc. Conjugates of dithiocarbamates with pharmacologically active agents and uses therefore
US6193973B1 (en) 1997-08-22 2001-02-27 B. David Tuttle Dietary supplement for boosting energy and increasing muscular strength
US5948628A (en) 1997-09-05 1999-09-07 The Board Of Regents Of The University Of Oklahoma Methods of screening for compounds which mimic galectin-1
WO1999043353A2 (fr) 1998-02-26 1999-09-02 Boehringer Ingelheim Pharmaceuticals, Inc. Therapie combinee par anti-selectine et immunodepresseur
US6265192B1 (en) 1998-03-20 2001-07-24 The Regents Of The University Of California Glycosly sulfortransferase-3
US6365365B1 (en) 1998-03-20 2002-04-02 The Regents Of The University Of California Method of determining whether an agent modulates glycosyl sulfotransferase-3
US6037333A (en) 1998-05-07 2000-03-14 Trustees Of Tufts College Microbe-inhibiting compositions
AU773542B2 (en) 1998-06-16 2004-05-27 Board Of Regents Of The University Of Oklahoma, The Glycosulfopeptides and methods of synthesis and use thereof
WO2000017216A1 (fr) 1998-09-21 2000-03-30 Otsuka Pharmaceutical Co., Ltd. Derives de carboxymethylgalactose
AU773174B2 (en) 1998-11-12 2004-05-20 Novolytics Inc. Compositions and methods for producing vascular occlusion
ATE321570T1 (de) 2000-05-19 2006-04-15 Blood Res Center Verfahren zur behandlung von hämostatischen störungen durch lösliches p-selectin
US20020132220A1 (en) 2000-12-27 2002-09-19 Berens Kurt L. Use of selectin antagonists in organ preservation solutions
US7087212B2 (en) 2001-08-17 2006-08-08 Mallinckrodt, Inc Multicomponent assemblies having enhanced binding properties for diagnosis and therapy
EP2264043B1 (fr) * 2005-09-02 2017-11-08 GlycoMimetics, Inc. Inhibiteurs de pan-selectine heterobifonctionnels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BÄNTELI R ET AL: "Potent E-Selectin Antagonists", HELVETICA CHIMICA ACTA, VERLAG HELVETICA CHIMICA ACTA, BASEL, CH LNKD- DOI:10.1002/1522-2675(20001108)83:11<2893::AID-HLCA2893>3.0.CO;2-G, vol. 83, 1 January 2000 (2000-01-01), pages 2893 - 2907, XP002257742, ISSN: 0018-019X *

Also Published As

Publication number Publication date
JP2010506832A (ja) 2010-03-04
JP5298020B2 (ja) 2013-09-25
CA2666103A1 (fr) 2008-05-22
WO2008060378A3 (fr) 2008-10-02
US7964569B2 (en) 2011-06-21
CA2666103C (fr) 2014-02-18
JP2013189471A (ja) 2013-09-26
EP2074132A2 (fr) 2009-07-01
US20110257380A1 (en) 2011-10-20
US20080161546A1 (en) 2008-07-03
WO2008060378A2 (fr) 2008-05-22

Similar Documents

Publication Publication Date Title
EP2074132B1 (fr) Replacements glycomimétiques pour des hexoses et des n-acétylhexosamines
JP5511390B2 (ja) ヘキソースおよびｎ−アセチルヘキソサミンの置換体を有する糖模倣体の使用方法
US9309276B2 (en) Synthetic lipid A derivative
JP3865411B2 (ja) 抗−エンドトキシン化合物
EP1232168B1 (fr) Analogues de lipide-a de synthese et leur utilisation
US20100063302A1 (en) Cyclic sulfonium salt, method for production of cyclic sulfonium salt, and glycosidase inhibitor
KR20150081220A (ko) 광학적으로 순수한 벤질-4-클로로페닐-c-글루코사이드 유도체
EP1232167A1 (fr) Oligomannosides de synthese, leur preparation et leurs utilisations
WO2015040140A1 (fr) Vaccins synthétiques sans protéine et sans peptide contre le streptococcus pneumoniae de type 3
EP1047703A1 (fr) Bibliotheque de combinaisons d&#39;analogues de moenomycine et procedes de production de ces analogues
CN107709343B (zh) 针对肺炎链球菌血清型5的疫苗
Hashihayata et al. Convergent total syntheses of oligosaccharides by one-pot sequential stereoselective glycosylations
WO2019151732A1 (fr) Composition pharmaceutique pour la prévention ou le traitement de complications du diabète comprenant un nouveau composé dérivé de chrysine en tant que principe actif
US6759390B2 (en) Compounds and their uses
US6716826B2 (en) Compounds and their uses
Mukherjee et al. Expeditious synthesis of the tetrasaccharide cap domain of the Leishmania donovani lipophosphoglycan using one-pot glycosylation reactions
WO2017071152A1 (fr) Phosphoryle mannose pentasaccharide et ses dérivés, procédé de préparation et utilisation correspondants
Zhang et al. The influence of the long chain fatty acid on the antagonistic activities of Rhizobium sin-1 lipid A
US6953781B2 (en) Compounds and their uses
JP2004217630A (ja) 右糖グルコースリピドａ類縁体
JPH0782292A (ja) 新規なグリチルレチン酸関連化合物又はそれらの塩
TW200413400A (en) Lipid a derivatives which have glucose back-bone as the reducing sugar part

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20090325

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

17Q First examination report despatched

Effective date: 20090720

DAX Request for extension of the european patent (deleted)
RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: GLYCOMIMETICS, INC.

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: AT

Ref legal event code: REF

Ref document number: 612110

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130615

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: DE

Ref legal event code: R096

Ref document number: 602007030516

Country of ref document: DE

Effective date: 20130711

REG Reference to a national code

Ref country code: AT

Ref legal event code: MK05

Ref document number: 612110

Country of ref document: AT

Kind code of ref document: T

Effective date: 20130515

REG Reference to a national code

Ref country code: LT

Ref legal event code: MG4D

REG Reference to a national code

Ref country code: NL

Ref legal event code: VDEP

Effective date: 20130515

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130915

Ref country code: ES

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130826

Ref country code: FI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: LT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: SI

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: SE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: GR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130816

Ref country code: AT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: PT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130916

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130815

Ref country code: PL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LV

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CZ

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: BE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: DK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: EE

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: SK

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: RO

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: IT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20140218

REG Reference to a national code

Ref country code: DE

Ref legal event code: R097

Ref document number: 602007030516

Country of ref document: DE

Effective date: 20140218

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131031

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131031

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131009

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CY

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

Ref country code: TR

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20131009

Ref country code: HU

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT; INVALID AB INITIO

Effective date: 20071009

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20130515

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 9

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 10

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 11

REG Reference to a national code

Ref country code: FR

Ref legal event code: PLFP

Year of fee payment: 12

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230514

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 20231027

Year of fee payment: 17

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 20231025

Year of fee payment: 17

Ref country code: DE

Payment date: 20231027

Year of fee payment: 17